We have investigated the role of one ets family member, ETS1, in the angiogenesis. Vascular endothelial growth factor (VEGF) increases the level of ETS1 mRNA and protein levels in human umbilical vein endothelial cells (HUVEC). VEGF was also found to stimulate the ability of HUVEC to migrate through Matrigel or gelatin coated membranes. This VEGF-induced invasiveness was inhibited by antisense ETS1 oligonucleotides but not by a sense or mismatch controls. Together, these observations demonstrate a direct role for the ETS1 gene in angiogenesis. We have established immortalized HUVEC by the HPV-16 E6-E7 genes and further transformed one immortalized but nontumorigenic line (4-5-2G) by v-Ki-ras to produce tumorigenic cell lines. E6 or E7 alone could not produce immortalized lines but extended the life span of the cells. 4-5-2G had a cobblestone morphology that developed into a capillary-like tube structure upon reaching confluence. It expressed factor VIII, took up DiI-Ac-LDL, and expressed integrin subunits in a pattern consistent with an endothelial origin. These results indicate that 4-5-2G may serve as a model for endothelial cell biology.